Schizophrenia is a psychiatric disorder with wide-ranging symptoms such as positive symptoms including delusion, hallucination and disorganized speech; negative symptoms including affective flattening, avolition, poverty of speech and social withdrawal; and cognitive impairment including deficits in attention, planning and abstract thinking and short and long term memory (Andreasen, N. C. et al, Lancet 346: 477˜481, 1995; Lewis, D. A., Liebermann, J. A., Neuron 28: 325˜334, 2000). The lifetime prevalence of schizophrenia is about 1%, which, in a global scale, amounts to 10 million sufferers. Family, twin, and adoption studies show that there is a relation between the lifetime risk for schizophrenia and genetic factors. This significant role that genetic factors play in the pathogenesis of schizophrenia was shown in linkage studies that identified strong candidate susceptibility genes and their loci (Gogos, J. A., Gerber, D. J., Trends Pharmacol. Sci. 27: 226˜233, 2006). Carriers of these candidate genes, however, do not necessarily exhibit the symptoms. Thus, these facts indicate that complex, interdependent genetic factors are involved in the connection between susceptibility genes and a full-blown disease. It is speculated that these genes may exert diverse influence on the core system so as to functionally heighten schizophrenia risks (Harrison, P. J., Weinberger, D. R., Mol. Psychiatry 10: 40˜68, image 45, 2005).
Animal models are important tools in understanding the neurobiology of complex brain diseases and serve as test subjects against which therapeutic efficacy of new drugs are evaluated. An animal model should display relevant endophenotypes, and the corresponding endophenotypes for a schizophrenia model would be locomotive hyperactivity, sensorimotor gating deficits, deficits in social interaction, and such cognitive impairments as in learning and memory (Braff, D. L., Freedman, R., Endophenotypes in studies of the genetics of schizophrenia. Lippincott Williams & Wilkens, 2002; Gould, T. D., Gottesman, I. I., Genes Brain Behav. 5: 113-119, 2006; van den Buuse, M. et al, Aust. NZ. J. Psychiatry 39: 550˜557, 2005).
Based on either current pathophysiological hypotheses (e.g. dopamine hypothesis) or known genetic linkages of schizophrenia, a few genetically modified mice targeting candidate susceptibility genes have so far been generated as animal models. These mouse models display at least one or more of the endophenotypes listed above (Gainetdinov, R. R. et al, Trends Neurosci. 24: 527˜533, 2001; Gerber, D. J. et al. Proc. Natl. Acad. Sci. 98: 15312˜15317, 2001; Kellendonk, C. et al., Neuron 49: 603˜615, 2006; Lijam, N. et al, Cell 90: 895˜905, 1997; Robertson, G. S. et al, J. Psychiatry Neurosci. 31: 157˜167, 2006; Yee, B. K. et al, Proc. Natl. Acad. Sci. 102: 17154˜17159, 2005); however, animal models simultaneously having multiple endophenotypes have not been developed.
Meanwhile, phospholipase C β1 (PLCβ1) hydrolyzes phosphatidylinositol 4,5-bisphosphate to yield diacyl-glycerol and inositol 1,4,5-trisphosphate (IP3), second messengers in the PLCβ1 signaling. β1 is the phospholipase C β isoform associated with G-protein-coupled receptors (GPCRs), which are known to be involved in many central nervous system (CNS) functions. PLCβ1 is expressed in select areas of brain such as cerebral cortex, hippocampus, amygdala, lateral septum, and olfactory bulbs (Watanabe, M. et al, Eur. J. Neurosci. 10: 2016˜2025, 1998). Such an expression profile suggests its implication in diverse critical brain functions including cognitive ones. Besides, a possible genetic association with schizophrenia has been reported in a linkage study of 20p12 (Arinami, T. et al, Am. J. Hum. Genet. 77: 937˜944, 2005), and abnormal expression patterns were observed in the brains of schizophrenics (Shirakawa, O. et al, Prog. Neuropsychopharmacol. Biol. Psychiatry 25: 867˜877, 2001).
With this supporting information at hand, the present inventors have developed a phospholipase C β1 knockout mouse (PLCβ1−/−) and confirmed its utility as an animal model of schizophrenia by carrying out various behavioral and neurological tests.